1. Technical Field
The present disclosure relates to systems for photo-processing of fluids, and more particularly to systems for photo-processing of complex fluids, such as blood products, pharmaceuticals, injectable solutions, and vaccines using non-laser light source(s) to generate and deliver monochromatic light at advantageous wavelength(s) in advantageous systems to affect desirable results.
2. Background of Related Art
Efforts have been devoted to treatment regimens for complex fluids, e.g., fluids having medical and/or health-related uses and applications, such as vaccines, pharmaceuticals, injectable solutions, blood products and the like. These efforts have focused in part on technologies and treatment systems to remove, inhibit and/or destroy unwanted fluid components. Treatment regimens aimed at alternative objectives, such as leukoreduction (i.e., the removal of white blood cells to avoid potentially undesirable effects), have also received attention.
Significant research and development attention has focused on fluids and materials that are collected for transfusion and/or transplantation, e.g., blood products and blood components. (“Pathogen Inactivation in Labile Blood Products” in Transfusion Medicine, Vol. 11, pp 149–175, 2001) In assuring the safety of such materials, significant reliance is placed on pre-transfusion donor evaluation and testing. Despite current efforts, transfusions and transplantations are nonetheless implicated in the transmission of viral, bacterial and protozoan diseases. New infectious agents continue to be identified in the donor population, giving rise to increased challenges and concerns among those responsible for ensuring a safe and reliable supply of needed transfusion/transplantation materials. Testing for unknown pathogens (e.g., HIV in the late 1970's) remains problematic. Moreover, limitations necessarily exist with respect to the effectiveness of donor screening efforts, e.g., donation volumes, screening/testing impediments, logistical issues, etc. Reliable screening and/or decontamination regimens are of even greater importance for individuals receiving multiple cycles of chemotherapy and/or hematopoietic transplantation because of the cumulative risk associated with repeated transfusion/transplantation episodes.
Current research activities and perspectives in the treatment of platelets are discussed in a recently published article. (L. Corash, “Inactivation of Viruses, Bacteria, Protozoa, and Leukocytes in Platelet Concentrates: Current Research Perspectives,” Transfusion Medicine Reviews, Vol. 13, No. 1, January, 1999). As noted in the article, risk associated with transfusion-associated infections could be reduced through development and implementation of decontamination processes that are effective against a broad array of infectious pathogens, regardless of type, including infectious agents not detected through current diagnostic tests. Decontamination processes are preferably effective against cell-free, cell-associated and latent pathogen forms. The need for this breadth in decontamination capability is exemplified by human immunodeficiency virus (HIV), which is cell-free in plasma, cell-associated in leukocytes, and in latent pro-viral form integrated into genomic leukocyte nucleic acid. Moreover, decontamination processes need to be active against a broad spectrum of bacteria, including intracellular bacterial forms, to avoid possible bacterial regrowth during storage.
Several potential inactivation technologies for treatment of platelet concentrates have been investigated/described, including psoralens activated with long-wavelength ultraviolet light, merocyanine 540 activated with visible light, riboflavin and methylene blue, and phthalocyanines activated with red light. Of these treatment technologies, attention has focused on the chemistry and associated bonding properties of different compounds, with psoralens receiving the greatest level of attention to date.
Psoralens are planar furocoumarins, many of which are synthesized by plants and ingested as foods. Psoralens preferentially bind to nucleic acid, both RNA and DNA, and vary widely with respect to solubility, nucleic acid affinity, and side reactions, e.g., active oxygen species generation. Investigations have shown that psoralen photochemical treatments can be effective for inactivation of bacteria, RNA viruses and DNA viruses. Exemplary psoralen compounds are described in U.S. Pat. No. 5,654,443 to Wollowitz et al.; U.S. Pat. No. 5,709,991 to Lin et al.; and U.S. Pat. No. 6,171,777 B1 to Cook et al.
Cerus Corporation (Concord, Calif.) has developed a series of psoralen componds that are being evaluated for their ability to inactivate pathogens in blood products. In one psoralen-based process under development by Cerus, a platelet suspension, which may be pooled from individual units from several donors, is transferred to a sterile disposable bag containing Cerus' S-59 psoralen compound. The blood-containing bag is illuminated with ultraviolet light for approximately three minutes. The Cerus procedure is intended to prevent the pathogen from reproducing and infecting a transfusion recipient. Cerus envisions the treated platelet suspension being ready for transfusion to a recipient.
The amount of psoralen required for efficient removal varies with the target species. Therefore, the inactivation levels achieved using photochemical treatment of blood products are a function of both UV dose and the concentration of the added chemical agent. The S-59 process, for example has a very strong dependence on the concentration of their proprietary psoralen, S-59. Pathogen inactivation requires 1000 times the amount of S-59 that leukocyte inactivation does. The range of UV doses required to accomplish the same task is smaller. Why? It may be that during the the experiments using S-59 it was not possible to adjust UV dose. More likely, the process is limited by the delivery of the chemical to the nucleic acid, not the activation of the chemical. From recent literature it appears that the efficacy of S-59 is limited by the kinetics of S-59 “uptake”. In biological material that readily absorbs S-59 the DNA is accessible and a lower doses of additive can be used. It is believed that this same process will limit all photochemical treatments including Inactine. Recent literature (see D. C. Hooper, Emerging Infectious Diseases (7)2, 2001) has found that certain species that are resistant to psoralen-like compounds have this resistance because they are able to modify their permeability to the toxin. This theory is also supported by lab findings using S-59 that show species specific log removal rates. Some of the species that are most resistant are the same ones identified in the Hooper reference. A similar issue is the accepted inability of S-59 to inactivate preformed spores. These spores are inactivated by UV. Therefore, a combination of direct activation by UV and by photochemical may be beneficial. This is similar to issues associated with cryptosporidium and chlorine in drinking water—crypto oocysts are not inactivated by chlorine, resulting in several outbreaks of cryptosporidiosis. Cryptosporidian is inactivated by UV.
This effect is also seen in systems using riboflavin as the photosensitizer (Goodrich et al., U.S. Pat. No. 6,277,337) developed by GAMBRO BCT. However, in this work inactivation is not only a function of the target pathogen, but also on dose and wavelength of the applied light. (It is possible that the wavelength of the light source will also effect the efficacy of psoralen based processes and that this effect has not been documented due to limitations in available light sources.) The riboflavin data presented in U.S. Pat. No. 6,277,337 shows that for some organisms, specifically double-stranded viruses, a combination of visible and UV light was needed. No explanations for this requirements were made. It is possible that the inactivation of the full range of pathogens may require more than one process.
Additionally, treatment modalities based on photochemical additives require, by definition, that an external agent/material be added to the fluid being treated, with the inherent issues and uncertainties associated therewith. Moreover, beyond the requirement that external agent(s)/material(s) be added to the fluid system to effect treatment, other limitations and/or requirements have been identified with respect to certain psoralen-based treatment modalities. For example, long treatment times (up to 4 hours of UVA illumination with 8-methoxypsoralen) and reduced ambient oxygen levels associated with certain psoralen-based systems are not compatible with requirements for ease of operation, e.g., in clinical blood bank environments. In addition, the addition of a free radical quencher, e.g., rutin (a naturally occurring flavenoid), may be required to prevent platelet damage due to active oxygen species, i.e., to preserve in vitro platelet function. The addition of free radical quencher(s) like rutin further increases the complexity of treatment systems.
As discussed by Corash, high UVA doses have also been required for certain psoralen compounds, e.g., from 24 to 70 J/cm2 for 4′-(amino-methyl)-4,5′,8-trimethlypsoralen (AMT), to treat platelet suspensions in 100% plasma. AMT has also exhibited questionable toxicology profiles. Reductions in plasma protein concentration, e.g., to 15% through use of synthetic platelet additive solution, is effective in reducing energy requirements, e.g., viral inactivation with AMT at 2.4 J/cm2, but is not practical for large-scale operations. (Transfusion Medicine Reviews, Vol. 13, No. 1, pp. 21, 23.)
Margolis-Nunno et al. evaluated the treatment of HIV-infected platelet concentrates with an AMT/rutin system using two types of ultraviolet radiation, UVA and UVA1. UVA was characterized as broad-band ultraviolet A light, having a wavelength of between 320 and 400 nm, and UVA1 was characterized as narrow-band UVA light, having a wavelength between 360 and 370 nm. Margolis-Nunno et al. concluded that wavelength was an important consideration in these treatment systems and that, at similar fluences, the tested UVA was more injurious to platelets than was UVA1. (Margolis-Nummo et al., “Psoralen-Mediated Photodecontamination of Platelet Concentrates: Inactivation of Cell-free and Cell-associated Forms of Human Immunodeficiency Virus and Assessment of Platelet Function In Vivo,” Transfusion, Vol. 37, September 1997, pp. 889–895.)
Photodynamic therapy (PDT) has also received significant research and development attention, particularly for cancer indications. In typical PDT treatment regimens, a photosensitizer is administered systemically, e.g., a porphyrin derivative, and after a period in which the photosensitizer accumulates within a target tissue, a measured amount of light is applied to the target region. Beyond cancer treatment, PDT treatments have been developed for use against ophthalmological conditions, cardiovascular conditions (e.g., artherosclerosis and restenosis), and immune-mediated conditions (e.g., psoriasis).
El-Ghorr and Norval describe the biological effects of narrow-band UVB irradiation, e.g., in treating psoriasis, as compared to conventional broadband UVB irradiation effects. (El-Ghorr et al., “Biological Effects of Narrow-Band (311 nm TL01) UVB Irradiation: A Review,” Journal of Photochemistry and Photobiology B: Biology 38 (1997), 99–106.) The TL01 lamp tested by El-Ghorr and Norval emits a narrow peak (51% of the radiant energy at 311 nm). Based on limited available test data, the TL01 lamp appears to be more suppressive than broad-band UVB during phototherapy with respect to natural killer cell activity and the function of mononuclear cells, as measured by lymphoproliferation and cytokine production. El-Ghorr and Norval suggest that the noted effect of the TL01 lamp may be both dose related and wavelength dependent.
In a further study, Prodouz et al. evaluated the use of laser-UV in treating blood products to inactivate poliovirus. (Prodouz et al., “Use of Laser-UV for Inactivation of Virus in Blood Products,” Blood, Vol. 70, No. 2, August, 1987, pp. 589–592.) The Prodouz et al. study uniformly irradiated samples with a XeCl excimer laser that delivered 40 nsec pulses of UV at 308 nm. This work noticed that at higher powers, including the very high peak power delivered from the pulsed laser, there was a greater reduction in platelet function. Even still, Prodouz et al. concluded that, when using a pulsed excimer laser at 308 nm, there exists a window of efficacy for exposure doses between 10.8 and 21.5 J/cm2 and peak intensities of less than 0.17 MW/cm2 within which a hardy virus is significantly inactivated and platelet and plasma proteins are minimally affected. This work inactivate polio virus. The efficacy of 308 nm on more complex targets has not been determined.
Andreu et al. evaluated ultraviolet irradiation of platelet concentrates to reduce HLA immunization by placing suspended platelet concentrates between quartz plates and irradiating with UV-B rays at 310 nm. Andreu et al. concluded that in vitro function of platelet concentrates remains unaffected by UV-B up to 2.25 J/cm2, but that higher energies inhibit the aggregation induced by ADP and collagen. Andreu et al. identified a gap in treatment effects with UV-B rays between 0.2 J/cm2, where the desired inhibitory effect on immunologic recognition is probably complete, and above 2 J/cm2, where detrimental effect on platelet function appears. (Andreu et al., “Ultraviolet Irradiation of Platelet Concentrates: Feasibility in Transfusion Practice,” Transfusion, Vol. 30, No. 5—1990, pp. 401–406.)
U.S. Pat. Nos. 4,726,949; 4,866,282; and 4,952,812 to Miripol et al. disclose blood product irradiation methods and systems for inactivating white blood cells. The Miripol et al. treatment regimens employ ultraviolet radiation predominantly of a wavelength of 280 to 320 nm, an intensity of 4 to 20 mW/cm2, and a total energy exposure of 800 to 20,000 mJ/cm2. Eight to twelve conventional, high intensity bulbs are described for use in irradiating blood contained within a flexible, collapsible poly(ethylene-vinyl) acetate plastic bag, the plastic bag typically being stretched on a framework. An exhaust fan is provided in the back of the Miripol et al. apparatus to exhaust heat generated by the high intensity bulbs. It is interesting to note that while in this work it was claimed that the process was novel because it operated at a different surface dose (J/cm2), a closer read of the data shows that the applied surface dose required for a successful treatment increases with the thickness of the blood product. The critical parameter is therefore not the applied surface dose, but how that dose is distributed within the fluid volume.
Despite efforts to date, there exists a continuing need for systems that facilitate treatment of complex fluids, e.g., blood products, pharmaceuticals, injectable solutions and vaccines. In particular, systems applicable to high value/complex fluids that effectively and reliably achieve desirable levels of pathogen inactivation, modulation of immune response, medical therapy and/or chemical synthesis, without negatively impacting desirable characteristics of the high value/complex fluid, are needed. While significant attention has been devoted to developing and evaluating a variety of photosensitive agents in treating pathogens and the like, the potential effects and/or influences of light source(s) and/or wavelength characteristics of light on complex fluid treatment systems have received less intensive study. While UV-B irradiation is considered an option for leukocyte inactivation pathogen using only UV light is not considered a viable process. Indeed, Cook et al. state that treatment of blood products to eliminate transmission of diseases by inactivating pathogens through UV alone is “completely incompatible with maintenance of red cell function.” (U.S. Pat. No. 6,171,777 B1, col. 2, lines 58–64.) A more recent review of “Pathogen Inactivation of Labile Blood Products (Transfusion Medicine, Vol. 11, 149–175, 2001), did not consider chemical free processing of pathogens using UV light.